Bisacchi in U.S. Pat. No. 6,335,324 explicitly discloses 3 guanidinoalkyl-2-azetidinones which have one of the following two structures:
wherein W is an unsubstituted 4-8 membered cycloalkyl ring; Y is either C═O or SO2; Z is either hydrogen or unsubstituted alkyl; RH can be any substitutent; and R2 can be any substituent.
Bisacchi in U.S. Pat. Pub. No. 2004/0147502 A1 explicitly discloses 1-[piperazinecarbonyl]azetidinones of the formula:
wherein R3 is any substituent, R4 is OH, NH2, alkyl or heteroalkyl, and R5 is any substituent.
Schumacher in U.S. Pat. Pub. No. 2004/0180855 A1 explicitly discloses methods of treating thrombosis in a mammal comprising administering a compound of the formula below that is selective for inhibition of Factor XIa.
wherein X is COOH, COOR, CONR, unsubstituted alkyl and unsubstituted arylalkyl, Y is CO or SO2, Z is H or unsubstituted alkyl, R2 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocycloalkyl.
Thrombo-embolic disorders are the largest cause of mortality (myocardial infarction) and disability (stroke) in the industrialized world. Arterial thrombosis is initiated by atherosclerotic plaque rupture, exposure of tissue factor, and initiation of the coagulation vortex. A number of coagulation factors are present in the blood as precursors (e.g., Factors VII-XII), and when the coagulation system is triggered, these factors undergo a complicated, ordered series of reactions that ultimately lead to thrombin production. Thrombin is a proteolytic enzyme that occupies a central position in the coagulation process. Thrombin catalyzes the conversion of fibrinogen to fibrin, is a key effector enzyme for blood clotting, and is also pivotal for other functions. High concentrations of thrombin inhibit fibrinolysis by activating the Thrombin Activated Fibrinolysis Inhibitor (TAFI), which can also be activated by modest amounts of thrombin in the presence of soluble or membrane bound thrombomodulin. TAFIa removes the C-terminal lysine residues from fibrin, preventing the binding of t-PA and plasmin and thus, slowing fibrinolysis.
The complicated coagulation process is initiated by tissue factor (TF). Tissue factor binds and activates Factor VII (FVII), which is rapidly converted to activated Factor VIIa (FVIIa) to form a TF:FVIIa complex. The TF:FVIIa complex activates Factors IX and X. Factor Xa generates small amounts of thrombin. The small amounts of thrombin activate Factor V, Factor VIII and platelets, accelerating thrombin production by Factors IXa and Xa. Activation of Factor V and FVIII accelerates catalytic activity of FVIIIa:FIXa and FVa:FXa, resulting in dramatically increased thrombin production. Another wave of thrombin generation occurs as a result of thrombin activation of Factor XIa. Factor XI activates more Factor IX. As the concentration of thrombin increases, more thrombin is generated, which in turn activates TAFI to then inhibit fibrinolysis.
This coagulation process involves an intrinsic pathway and an extrinsic pathway. In the intrinsic pathway, Factor XII (aka Hageman Factor) is converted from its inactive form (zymogen) to an active form, i.e., Factor XIIa. Activated Factor XII enzymatically activates Factor XI to Factor XIa. Activated Factor XI activates Factor IXa. Factor IXa then converts Factor X to Factor Xa. FXa activates prothombin to thrombin. Thrombin cleaves fibrinogen to form insoluble fibrin (the clot). In the extrinsic pathway, addition of thromboplastin (i.e., tissue factor) to plasma activates Factor VII. This complex, in the presence of calcium ions and phospholipids, activates Factor X to Factor Xa. Once Factor Xa is generated, the remainder of the cascade is similar to the intrinsic pathway. As can be seen, Factor XIa is involved only in the intrinsic pathway.
In vitro, the degree to which FXIa contributes to thrombin generation, platelet activation, and fibrin formation depends on the concentration of tissue factor. For example, in the absence of FXI (i.e., in FXIa deficient plasma), plasma stimulated with low levels of tissue factor (clot formation>10 minutes) showed a delay in the time required to generate thrombin and form clots. A FXI deficiency also decreased the amount of thrombin generated and platelet aggregation in whole blood. However, in blood or plasma stimulated by higher concentration of tissue factor (clot formation<5 minutes), a FXI deficiency had no effect on the thrombin generation or clot formation. Thus, a FXI deficiency will generally prolong thrombin generation but not in situations where the plasma is stimulated with high concentrations of tissue factor.
FXIa, via expanded thrombin generation, also plays a role in resisting fibrinolysis. Resistance of plasma clots to tPA and uPA-induced fibrinolysis depends on thrombin concentration (generated endogenously or added exogenously) in the plasma. The time required for clot lysis is proportional to the plasma TAFIa concentrations. However, clot lysis can occur more rapidly, and the lysis made independent of plasma TAFI concentration, when blocking antibodies to FXIa are included in the assay.
Elevated levels of FXIa in the plasma and/or increased activation of FXIa is associated with various cardiovascular and other diseases. As an illustration, increased activation of FXIa occurs in patients with coronary artery disease and is related to the severity of the disease. Also, Factor IX activation peptide (a product of FXIa and TF:FVIIa cleavage of FIX) levels have been found to be significantly higher in patients with acute myocardial infarction and unstable angina compared with patients with stable angina. Concentrations of FXIa-α1AT (FXIa complexed to the serpin α1-antitrypsin) were also elevated in patients with recent myocardial infarction or unstable angina. Patients with high levels of Factor XI are at risk for deep venous thrombosis.
Proteins or peptides that reportedly inhibit Factor XIa are disclosed in WO 01/27079 to Entremed, Inc. There are advantages in using small organic compounds, however, in preparing pharmaceuticals, e.g., small compounds generally have better oral bioavailability and compatibility in making formulations to aid in delivery of the drug as compared with large proteins or peptides. Small organic compounds have been disclosed that reportedly inhibit coagulation factors besides Factor XIa. For example, compounds effective in inhibiting Factor Xa are described in U.S. Pat. Nos. 6,344,450 and 6,297,233, and WO 00/47563. Compounds effective in inhibiting Factors VIIa, Xa, as well as tryptase and urokinase are described in U.S. Pat. No. 6,335,324. Factor Xa inhibitors are disclosed in WO 98/57937 to the duPont Merck Pharmaceutical Co., and Factor VIIa inhibitors are disclosed in U.S. Pat. No. 6,358,960 to Ono Pharmaceuticals Inc., (“Ono”), and in WO 01/44172 to Axys Pharm. Inc.
A possible adverse side effect associated with use of anti-thrombotic agents for treating cardiovascular diseases involves the risk of bleeding. For example, heparin is a known anti-thrombotic agent that has a highly-variable dose-related response, and its anticoagulant effects must be closely monitored to avoid a risk of serious bleeding. The erratic anticoagulant response of heparin is likely due to its propensity to bind non-specifically to plasma proteins. Aspirin also has been used as an anti-thrombotic agent but at high doses presents a risk of gastrointestinal bleeding. Thrombin inhibitors and their drawbacks are further discussed in WO 96/20689 to duPont Merck Pharmaceutical Co. Guanidine and beta lactam-containing compounds that are potent inhibitors of serine proteases including thrombin and tryptase are described in U.S. Pat. No. 6,335,324, the entire contents of which is incorporated herein by reference.